Atherosclerosis

Question 1

Explain the exogenous pathway of lipid metabolism

Answer 1

1. Dietary triglycerides and cholesterol broken down and packaged into chylomicrons
2. Chylomicrons broken down into FFAs and chylomicron remnants
3. These products end up in adipose tissue, muscle and BVs (pro-inflamm)
4. Chylomicron remnants can bind to LDLR on liver and be taken up

Question 2

What drugs are used to prevent and treat atherosclerosis and the subsequent rupture of an atherosclerotic plaque?

Answer 2

Statins: 1st line for dyslipidaemia; lower LDL

Bile acid sequestrants: lower cholesterol

Nicotinic acid: increase HDL

Fibrate: lower triglyceride

Question 3

Explain the endogenous pathway of lipid metabolism

Answer 3

Most circulating lipids are endogenous (made by liver)

1. TG and cholesterol ester generated by liver
2. Packaged into VLDL particles and released into circulation
3. VLDL processed by LPL in tissues to release FAs + glycerol
4. VLDL –> VLDL remnant –> IDL
5. Majority of remnants + IDL taken up by liver via LDLR and repackaged as LDL

Question 4

Summarise the pathogenesis of atherosclerosis

Answer 4

1. LDL gets into endothelium
2. Endothelium becomes dysfunctional
3. Release of GFs and cytokines, which attract inflamm cells (monocytes)
4. Formation of foam cells in endothelium (macrophages w lots of lipid)
5. Proliferation of fibroblasts and SMCs expands the plaque

Question 5

What is the earliest recognisable lesion of atherosclerosis?

Answer 5

Fatty streak

Question 6

What causes fatty streak formation?

Answer 6

Aggregation of lipid-rich foam cells (derived from macrophages and T cells within tunica intima)
Later, SMCs migrate and are added to lesion
Form in direction of blood flow

Question 7

Explain the formation of a complicated atherosclerotic plaque

Answer 7

1. Death and rupture of foam cells in fatty streak
2. Formation of necrotic core
3. Migration of SMCs into intima + laying down of collagen fibres –> protective fibrous cap formed over lipid core
4. Cap separates thrombogenic lipid-rich core from circulating platelets and CFs

Question 8

How are stable atherosclerotic plaques characterised?

Answer 8

Necrotic lipid core covered by thick vascular smooth muscle-rich fibrous plaque

Question 9

What’s the link between calcium content of the plaque and symptoms?

Answer 9

The more calcium in the plaque, the more likely it is that the patient is symptomatic

Question 10

How are vulnerable atherosclerotic plaques characterised?

Answer 10

Thin fibrous cap
Core rich in lipids and macrophages
Less evidence of smooth muscle proliferation

Question 11

With what events is plaque rupture associated?

Answer 11

Greater influx and activation of macrophages

Release of matrix metalloproteinases involved in collagen breakdown

Question 12

How do lipids play a role in atherosclerosis?

Answer 12

1. LDL cholesterol strongly associated w/atherosclerosis and CHD events - 10% increase in LDL increases CHD risk by 20%
2. HDL cholesterol has protective effect
3. Triglycerides - may be related to low HDL levels and more atherogenic forms of LDL

Question 13

What are the clinical manifestations of atherosclerosis?

Answer 13

1. Coronary heart disease - angina pectoris, MI, sudden cardiac death
2. Cerebrovascular disease - transient ischaemic attacks, stroke
3. Peripheral vascular disease- intermittent claudication, gangrene